Fuller, Collin

Guerrieri, Courtney

Hirokawa, Dawn

Lee, MD, Jason B.

McGeehin, Eleni

Sethi, Mansha

Sherban, Alex

Yang, Sherry

Jefferson Digital Commons

Thomas Jefferson University Jefferson Digital Commons Department of Dermatology and Cutaneous Biology Faculty Papers Department of Dermatology and Cutaneous Biology 12-1-2020 Bullous hemorrhagic Sweet syndrome with cryptococcoid neutrophils in patients positive for antineutrophil cytoplasmic antibody without primary vasculitis. Alex Sherban Collin Fuller Mansha Sethi Eleni McGeehin Dawn Hirokawa See next page for additional authors Follow this and additional works at: https://jdc.jefferson.edu/dcbfp  Part of the Dermatology Commons Let us know how access to this document benefits you This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Dermatology and Cutaneous Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: JeffersonDigitalCommons@jefferson.edu. Authors Alex Sherban; Collin Fuller; Mansha Sethi; Eleni McGeehin; Dawn Hirokawa; Courtney Guerrieri; Jason B. Lee, MD; and Sherry Yang CASE SERIESBullous hemorrhagic Sweet syndrome withcryptococcoid neutrophils in patients positivefor antineutrophil cytoplasmic antibody withoutprimary vasculitisAlex Sherban, BM,a Collin Fuller, MD,b Mansha Sethi, MD,b Eleni McGeehin, MD,bDawn Hirokawa, MD, MPH,c Courtney Guerrieri, MD,c Jason Lee, MD,b and Sherry Yang, MDbPhiladelphia, Pennsylvania and Newark, DelawareKey words: clinical research; cryptococcoid neutrophils; general dermatology; hemorrhagic bullae; medicaldermatology; neutrophilic dermatoses; p-ANCA; Sweet syndrome; vasculitis.INTRODUCTIONSweet syndrome (SS) is a febrile neutrophilicdermatosis characterized by pyrexia, peripheralleukocytosis, and an abrupt onset of painfulerythematous plaques and nodules.1,2 Lesions aretypically found in an asymmetric distribution on theface, neck, and upper extremities and are oftenassociated with an underlying malignancy, asystemic inflammatory condition, or a precedinginfection.1,2 Histopathologic examination reveals adense neutrophilic infiltrate with papillary dermaledema, and serum laboratory tests show leukocy-tosis, an elevated erythrocyte sedimentation rate, orboth.1,2 Atypical bullous or hemorrhagic presenta-tions have been described in the literature, with themajority in a setting of hematologic malignancy.3-7Twenty percent of patients with SS have anunderlying malignancy that can manifest withatypical bullae.8Herein, we describe 3 patients with hemorrhag-ic SS and cryptococcoid-appearing neutrophils onhistopathologic examination, all of whom werefound to be positive for antineutrophil cytoplasmicantibodies (ANCA) and negative for malignancy.This constellation of findings has rarely beendescribed in the literature and raises newdiagnostic and prognostic considerations for SSpatients presenting with a hemorrhagic or bullousmorphology.CASE DESCRIPTIONSCase 1A 70-year-old Caucasian woman with end-stagerenal disease, diabetes, and chronic obstructivepulmonary disease presented to an outside hospitalwith fever, nausea, vomiting, and abdominal pain.Head computed tomography demonstrated a softtissue swelling of the subcutaneous layer along theright parotid and submandibular glands, consistentwith a subcutaneous infection, while chest X-rayrevealed bilateral infiltrates. A culture of bronchialwashings was positive for Pseudomonas. She wasdiagnosed with bilateral pneumonia complicated byseptic shock and an infection of the parotid andsubmandibular glands before the development ofhemorrhagic bullae on her face and arms.Subsequently, respiratory distress requiring intubationdeveloped, and shewas transferred toour hospital. Shereceived multiple antibiotics, including vancomycin,cefepime, doxycycline, cephalexin, cefazolin, andpiperacillin/tazobactam, prior to the transfer. Physicalexamination showed erythematous to violaceous tensehemorrhagic bullae on her face, neck, upper portion ofAbbreviations used:ANCA: antineutrophil cytoplasmic antibodySS: Sweet syndromeFrom the Sidney Kimmel Medical College,a Department of Derma-tology and Cutaneous Biology,b Thomas Jefferson University,Philadelphia, Pennsylvania, and Department of Dermatology,cChristianaCare Health Systems, Newark, Delaware.Funding sources: None.Conflicts of interest: None disclosed.IRB approval status: Not applicable.Correspondence to: Sherry Yang, MD, 833 Chestnut Street, Suite740, Philadelphia, PA 19107. E-mail: Sherry.yang@jefferson.edu.JAAD Case Reports 2020;6:1196-200.2352-5126 2020 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).https://doi.org/10.1016/j.jdcr.2020.10.0061196the chest, both arms, dorsal surface of the hands, andlateral aspect of the fingers (Figs 1 and 2). The differ-ential diagnosis included atypical SS versus bulloussmall-to-mediumevessel vasculitis. A biopsy of theupper portion of the right arm showed a denseneutrophilic infiltrate in the mid-dermal layer withpapillary dermal edema (Figs 3 and 4). The bloodvessels appeared to be intact. The neutrophils in thedermis exhibited prominent vacuolated cytoplasm.Gram, Grocott methenamine silver, and periodicacideSchiff stains were negative for micro-organisms.Direct immunofluorescence test result was negative forIgG, IgM, IgA, andC3. ANCA test result was positive forperinuclear antineutrophil cytoplasmic antibody (p-ANCA), with titers elevated at [1:640. Proteinase 3antibodies were also elevated at 123.4 (normal range,0-20). Based on these findings, shewas diagnosedwithSS. Rheumatology andhematology/oncologyworkupsfailed to reveal the underlying cause. She was startedondapsoneanda slowprednisone taper,with eventualclearance of her skin lesions.Case 2A 68-year-old Caucasian woman with chronicanemia, hypertension, and hypercholesterolemia,was admitted and intubated for a retropharyngealabscess and respiratory distress as well as hemor-rhagic papules and plaques on her face, arms, hands,legs, and eyelids. The patient was successfullyextubated,with the resolution of her retropharyngealabscess following the administration of intravenousantibiotics. Biopsies of the left arm and hand demon-strated dense neutrophilic infiltrates with leukocyto-clasis andfibrin deposition, suggesting vasculitis. Thedifferential diagnosis included neutrophilicFig 1. SS with erythematous to violaceous tense hemor-rhagic bullae in the right antecubital fossa of patient 1. SS,Sweet syndrome.Fig 2. SS with violaceous tense bullae and focal erosionson the dorsal surface of the left hand of patient 1. SS, Sweetsyndrome.Fig 3. SS punch specimen from the right antecubital fossashowing a dense mixed-cell infiltrate in the superficialdermis. (Hematoxylin-eosin stain; original magnification:310). SS, Sweet syndrome.Fig 4. SS punch specimen from the right antecubital fossashowing many nuclei with prominent cleared-out spacehaving an encapsulated appearance. (Hematoxylin-eosinstain; original magnification: 340). SS, Sweet syndrome.JAAD CASE REPORTSVOLUME 6, NUMBER 12Sherban et al 1197dermatosis with secondary vasculitis, primary small-vessel vasculitis, or a pustular drug eruption. PeriodicacideSchiff stain, acid-fast bacilli test,Gramstain, andtissue cultures were negative for infectious organ-isms, while direct immunofluorescence test failed toreveal vasculitis. The patientwas positive for p-ANCAand negative for cytoplasmic antineutrophil cyto-plasmic antibody (c-ANCA). Myeloperoxidase anti-bodies were elevated at 6.0 (negative \ 0.4).Proteinase 3 antibodies were equivocal at 0.7(negative \ 0.4, equivocal 0.4-0.9). Hematology/oncology, rheumatology, and infectious diseaseworkups were negative. Based on the negative directimmunofluorescence test result, p-ANCA positivity,and histologic neutrophilic infiltrate, the patient wasdiagnosed with SS with secondary vasculitis. She wastreatedwithprednisone,mycophenolatemofetil, anddapsone, but she ultimately dieddue to urosepsis andmultiorgan failure.Case 3A 70-year-old Caucasian woman with end-stagerenal disease, diabetes, and recent cardiac catheter-ization was admitted for respiratory syncytial viruspneumonia. She was found to have painfululcerations of varying durations on her head, upperextremities, and tongue. She denied having fevers,chills, changes in vision, weight loss, or cocaine use.Examination showed a crusted, hemorrhagicgranulation tissue on the bilateral triangular fossae(Fig 5). The posterior part of the left forearm, plantarsurface of the index fingers, and the left side of thetongue showed deeply erythematous to violaceousexudative plaques and papules with hemorrhage.The differential diagnosis included calciphylaxis,cholesterol emboli, and neutrophilic dermatoses.Without intervention, she reported a progression inthe number of lesions, with new painful, purpuricpapules on her hands and elbows and worsening ofthe existing lesions.A biopsy of the upper part of the left ear showed adense neutrophilic infiltrate, without the evidence ofvasculitis or fungal infection. A biopsy of the right earlater showed a dense neutrophilic infiltrate withcryptococcoid-appearing bodies, which was furtherdescribed as a dense neutrophilic infiltrate (Fig 6).Gram stain and tissue culture for acid-fast bacilli andfungi failed to reveal an infectious cause.Myeloperoxidase antibody titers were elevated at[0.8 (negative \ 0.4). Antinuclear antibody titerswere 1:320 in a homogeneous pattern. Antihistoneantibody titers were elevated at 2.6 (negative\1.0).Extractable nuclear antigen ribonucleoprotein IgGantibody titerswere elevatedat[8.0 (negative\1.0).Proteinase 3 antibody titers were negative at \0.2(negative\0.4). The patient was diagnosed with SS,and she improved following the initiation of predni-sone, dapsone, and mycophenolate mofetil.DISCUSSIONWe present a case series linking rare findings thathave not been previously reported together in SS.Three elderly Caucasian women presented withbullous hemorrhagic lesions that were temporallyrelated to infections. Further investigation revealedthat each patient was positive for ANCA, withvacuolated basophilic bodies on the biopsy and thehistologic evidence supporting vasculitis. Whilethese findings have been reported independently,this is the first time, to our knowledge, that all 3 havebeen reported in a similar population. We predictFig 5. SS showing a crusted, hemorrhagic granulationtissue and violaceous plaque on the right ear of patient 3.SS, Sweet syndrome.Fig 6. SS punch specimen from the right ear showing adense infiltrate consisting of neutrophils and their nucleardust and lymphocytes. (Hematoxylin-eosin stain; originalmagnification: 339). SS, Sweet syndrome.JAAD CASE REPORTSDECEMBER 20201198 Sherban et althat these atypical findings are associated and have acausal relationship.The bullous variant of SS presents with hemor-rhagic bullae and splitting of the dermoepidermaljunction.3-5 The marked activation of the neutrophilsand subsequent tissue destruction may be related tothe expression of CD3, CD163, tumor necrosisfactor-a, interleukin (IL) 8, IL-17, matrixmetalloproteinase-9, and myeloperoxidase.4 Thisextensive destruction by the neutrophils may becompounded in patients positive for ANCA. Bothc-ANCA and p-ANCA have been seen in SS.4,5The absence of vasculitis has been a hallmark ofSS. However, a study by Malone et al investigatingthe association between vasculitis and SS found that21% of patients in the study met the diagnosticcriteria for vasculitis, not including patients withsigns of vessel damage without fibrinoid necrosis.9The study proposed that vasculitic changescould be secondary to neutrophil activation anddegranulation, not immune complex deposition.9SS may induce secondary vasculitis.10 A casereport of neutrophilic dermatosis of the dorsalsurface of the hands found the patient to be positivefor p-ANCA, with a decrease in the level of p-ANCAcorresponding to the ‘‘clinical activity of thedermatoses,’’ suggesting a correlation betweenneutrophilic dermatosis and ANCA.10The presence of ANCA without autoimmunevasculitis has been noted in the literature. In aretrospective analysis of patients positive for ANCA,60.2% of the 113 patients positive for c-ANCA orp-ANCA had no evidence of ANCA-associatedvasculitis.11 There are several etiologies associatedwith ANCA positivity without vasculitis, includinginfectious diseases.11Another report of a patient with SS suggestedthat the patient, initially negative for ANCA,became positive for ANCA because of abnormalneutrophil fragmentation and degradation, allow-ing the normally sequestered intracellular contentsof the neutrophils to be exposed to the immunesystem, leading to ANCA generation.12 Otherstudies have hypothesized that fragmented neu-trophils and the release of neutrophilic antigensmay be responsible for the development of ANCAin patients with SS.13While SS can be a harbinger of vasculitis positivefor ANCA-positive vasculitis, the detection of circu-lating ANCA more likely results from the intenseneutrophil degradation in the setting of SS triggeredby an infectious etiology, as demonstrated by thiscase series. The lack of small-to-mediumevesselinvolvement in other organ systems and improve-ment of ANCA titers corresponding to the resolutionof SS can be helpful indicators against a diagnosis ofprimary ANCA vasculitis.A histologic variant of SS exists when the neutro-philic dermal infiltrate surrounds vacuolated spaceswith basophilic bodies, mimicking the encapsulatedappearance of cryptococcal infections.6,7,14,15 Theseacellular, cryptococcoid bodies are thought to be dueto degenerating neutrophils within the neutrophilicinfiltrate.6,14,15 Their basophilic component stainssimilar to the nuclei of the surrounding neutrophils,with negative fungal stains.6Our hypothesis states that there are likely varyingdegrees of SS, and the infections that each of ourpatients experienced led to an acute, exuberantstimulation of the neutrophils. We believe that thevacuolated spaces or cryptococcoid appearanceseen on the biopsy represented rapidly degeneratingneutrophils that led to abundant neutrophilicantigens and the resultant production of ANCAwithout true autoimmune vasculitis. Thecryptococcoid-appearing neutrophils and ANCApositivity may portend a more clinically aggressivepresentation of SS. In the absence of other riskfactors or laboratory abnormalities, providers shouldconsider these findings as a representation ofinfection-induced hemorrhagic SS rather thanpursuing an aggressive workup for an underlyingmalignancy. Further studies are needed to fullyunderstand the relationships among these rarefindings.REFERENCES1. Cohen PR. Sweets syndrome e A comprehensive review of anacute febrile neutrophilic dermatosis. Orphanet J Rare Dis.2007;2(1):34.2. Rochet NM, Chavan RN, Cappel MA, Wada DA, Gibson LE.Sweet syndrome: clinical presentation, associations, andresponse to treatment in 77 patients. J Am Acad Dermatol.2013;69(4):557-564.3. Voelter-Mahlknecht S, Bauer J, Metzler G, Fierlbeck G,Rassner G. Bullous variant of Sweets syndrome. Int J Dermatol.2005;44(11):946-947.4. Bhat AG, Malleshappa SKS, Pasupula DK, Duke W, Shaaban R.Bullous variant of Sweet syndrome as a consequence ofradioiodine contrast exposure. Cureus. 2018;10(10):e3490.5. Lund JJ, Stratman EJ, Jose D, Xia L, Wilson D, Moizuddin M.Drug-induced bullous Sweet syndrome with multiple autoim-mune features. Autoimmune Dis. 2010;2010:1-4.6. Ko JS, Fernandez AP, Anderson KA, et al. Morphologicmimickers of Cryptococcus occurring within inflammatoryinfiltrates in the setting of neutrophilic dermatitis: a series ofthree cases highlighting clinical dilemmas associated with anovel histopathologic pitfall. J Cutan Pathol. 2012;40(1):38-45.7. Wilson TC, Stone MS, Swick BL. Histiocytoid Sweet syndromewith haloed myeloid cells masquerading as a cryptococcalinfection. Am J Dermatopathol. 2014;36(3):264-269.8. Kinser KN, Panach K, Dominguez AR. Recurrent malignancy-associated atypical neutrophilic dermatosis with noninfectiousshock. Am J Med Sci. 2017;354(6):626-632.JAAD CASE REPORTSVOLUME 6, NUMBER 12Sherban et al 11999. Malone JC, Slone SP, Wills-Frank LA, et al. VascularInflammation (vasculitis) in Sweet syndrome. Arch Dermatol.2002;138(3):345-349.10. Malik M, Perkins W, Leach I. Anti-neutrophil cytoplasmicantibody-positive neutrophilic dermatosis of the dorsal hands.Clin Exp Dermatol. 2012;37(8):869-870.11. Bornstein G, Ben-Zvi I, Furie N, Grossman C. Clinicalsignificance of positive anti-neutrophil cytoplasmic antibodieswithout evidence of anti-neutrophil cytoplasmic antibodies-associated vasculitis. Int J Rheum Dis. 2019;22(5):940-945.12. Darne S, Natarajan S, Blasdale C. Do antineutrophilcytoplasmic antibodies (ANCA) play a key role in neutrophilicdermatoses? A case of propylthiouracil-induced neutrophilicdermatosis with positive perinuclear ANCA. Clin Exp Dermatol.2010;35(4):406-408.13. Kemmett D, Harrison D, Hunter J. Antibodies to neutrophilcytoplasmic antigens: a serologic marker for Sweetssyndrome. J Am Acad Dermatol. 1991;24(6):967-969.14. Wilson J, Gleghorn K, Kelly B. Cryptococcoid Sweets syndrome:Two reports of Sweets syndrome mimicking cutaneouscryptococcosis. J Cutan Pathol. 2017;44(5):413-419.15. Berg S, Cummings L. Sweet syndrome histologically mimickingcutaneous cryptococcus. J Am Acad Dermatol. 2019;81(4):AB281.JAAD CASE REPORTSDECEMBER 20201200 Sherban et al

Bullous hemorrhagic Sweet syndrome with cryptococcoid neutrophils in patients positive for antineutrophil cytoplasmic antibody without primary vasculitis.

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Bullous hemorrhagic Sweet syndrome with cryptococcoid neutrophils in patients positive for antineutrophil cytoplasmic antibody without primary vasculitis.

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